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Abstract

Rationale: Lymphatic vasculature constitutes a second vascular system, essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly-branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown.

Objective: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development.
Methods and Results: We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that, although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2, a transcription factor involved in lymphatic remodeling, was decreased in PPolydom-/- mice. Polydom bound to the lymphangiogenic factor Angiopoietin-2, which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for Angiopoietins were also decreased in Polydom-/- mice.